The delivery of drugs and drug precursors by diffusion through the skin offers improvements over more traditional delivery methods, such as subcutaneous injections and oral delivery. Transdermal drug delivery by passive diffusion avoids the hepatic first pass effect encountered with oral drug delivery. Passive transdermal drug delivery also reduces patient discomfort when compared to subcutaneous injection, and provides more uniform drug blood concentrations over time. The term "transdermal" delivery, broadly encompasses the delivery of an agent through a body surface, such as the skin, mucosa, or nails of an animal or the outer surface of a plant.
The skin functions as the primary barrier to the transdermal penetration of external substances into the body and represents the body's major resistance to the delivery of agents. Up to the present time, most efforts have been focussed on reducing the physical resistance or enhancing the permeability of the skin to the delivery of the therapeutic agent being delivered. Various methods for increasing the rate of transdermal drug diffusion have been used. For example, drug-impermeable backing layers made of metal, plastic and other materials have been employed in skin patches in order to limit diffusion of drugs away from the skin and, thereby, increase the diffusion of drugs into the skin. In addition, an increase in the rate of absorption of agents into the skin was produced by varying the temperature and the relative humidity of the atmosphere adjacent to the skin. Other efforts have been directed at abrading or piercing the skin by mechanically disrupting its outermost stratum corneum layer. Chemical absorption promoters or permeation enhancers have also been utilized, both as integral components of therapeutic compositions or applied prior to the therapeutic agent. These passive methods have generally proven ineffective in significantly increasing the amount of agent delivered, particularly in the case of hydrophilic drugs (eg, in the form of water soluble salts) and high molecular weight agents (eg, polypeptides and proteins).
"Electrotransport" involves the delivery of a agent through a body surface with the assistance of an electrical field. Electrotransport, thus, refers generally to the passage of an agent through a substrate, such as the skin, mucous membranes, or nails, which is at least partially induced by circulating an electrical current through the substrate. Many agents, including therapeutic drugs and precursors thereof, may be introduced into the human body by electrotransport. The electrotransport of an agent through a body surface may be attained by various methods. One widely used electrotransport method is iontophoresis, which involves the electrically induced transport of charged ions. Electroosmosis, another type of electrotransport, involves the movement of a liquid out of, or through, a biological membrane under the influence of an electrical field. Electroporation, still another type of electrotransport, involves the movement of an agent through transiently-created pores formed in a biological membrane under the influence of an electric field. When any given agent is electrotransported, more than one of these methods may occur simultaneously to some extent. The term electrotransport, as used herein, is given its broadest possible interpretation to include the electrically induced or enhanced transport of charged and uncharged agents or mixtures thereof, regardless of the specific mechanism(s) by which the agent(s) is(are) actually transported.
Electrotransport devices typically require at least two electrodes, both being in electrical contact with some portion of the skin, nails, mucous membrane, or other membrane surfaces of the body. One electrode, commonly referred to as the "donor" or "active" electrode, is the electrode from which an agent, such as a drug or drug precursor, is delivered into the body. The other electrode, typically termed the "counter" or "return" electrode, serves to close the electrical circuit through the body. For example, if the ionic agent to be delivered is a cation, i.e. a positively charged ion, the anode will be the active or donor electrode while the cathode completes the circuit. Alternatively, if the agent is an anion, ie, a negatively charged ion, the cathode will be the donor electrode while the anode completes the circuit. When anionic and cationic drugs need to be delivered at the same time, both the anode and cathode may be used for this purpose and the anionic drug placed in the cathode while the cationic drug is placed in the anode. In addition, electrotransport delivery devices typically include an electrical power source in the form of one or more batteries, and an electrical control mechanism designed to regulate the flow of electric current through the electrodes and thereby the rate of drug delivery. Alternatively, the power may be supplied, at least in part, by a galvanic couple formed by contacting two electrodes made of dissimilar materials. A complete electrical circuit is formed by electrically contacting one pole of the power source to the donor electrode, the donor electrode to the body, the body to the counter electrode, and the counter electrode to the opposite pole of the power source. The donor electrode typically includes a reservoir or source of the agent or drug to be delivered. The donor reservoir may take the form of a pouch, a cavity, a porous sponge, a pad, and a pre-formed gel body, among others. The counter electrolyte likewise typically includes a reservoir containing a biocompatible electrolyte. Such reservoirs are electrically connected to the anode or cathode of the electrotransport device to provide either a fixed or a renewable source of one or more electrolytes, therapeutic agents or drugs.
It is known that electrotransport drug flux is roughly proportional to the level of electric current applied by the device. However, there is a limit to the amount of current which may be comfortably tolerated by a patient. This problem becomes more acute as the size of the electrotransport system and, therefore, the skin contact areas of the electrodes is reduced, as is the case in portable/wearable systems. As the skin contact area of an electrotransport device decreases, the current density, (ie, the amount of current per unit of skin contact area) applied by the device increases. Thus, there is a limit to the level of electric current which may be applied by any electrotransport device of a given size and, this current limit becomes lower as the size (ie, the skin contact area) of the device is reduced. In certain instances, electrotransport devices operating at these current limits have been unable to deliver sufficient amounts of drug to effectively treat a disease. In those cases, the incorporation of a permeation enhancer into the electrotransport device may increase the amount of the drug delivered, and help maintain a higher and therapeutically effective concentration of drug in the blood. In the context of this application, the terms "permeation enhancer" include absorption promoters and surfactants and broadly describe a chemical species which either reduces the physical resistance of a body surface to the passage of an agent therethrough or, as electrotransport enhancers do, alters the ionic selectivity of the body surface, increases the electrical conductivity or the permeability of the body surface, and/or the number of agent-transmitting pathways therethrough. The use of electrotransport enhancers may also help reduce the size of the electrotransport device by requiring a reduced total electric current and thereby a reduced electrode skin-contact area for achieving a particular current density. A reduction in the size of the device will also, most likely, improve patient comfort and reduce manufacturing costs.
A limited number of electrotransport enhancers for the delivery of agents have been disclosed in the literature. Ethanol, for instance, has been utilized as an electrotransport enhancer for polypeptides by Srinivasan et al., (Srinivasan et al, "Iontophoresis of Polypeptides: Effect of Ethanol Pretreatment of Human Skin", J Pharm Sci 79(7):588-91 (1990)). In U.S. Pat. No. 4,722,726 to Sanderson et al., the skin surface is pretreated with a surface active agent prior to the application of the drug to the skin to reduce competition with tissue ions migrating outwardly through the skin, with sodium lauryl sulfate being a preferred surface active agent. U.S. Pat. No. 5,023,085 to Francoeur et al. discloses the use of unsaturated C.sub.14 -C.sub.20 acids, alcohols, amines, and esters, along with ketones for the iontophoretic delivery of certain drugs. Laid Open Patent Application WO91/16077 discloses the use of fatty acids, such as oleic acid, lauric acid, capric acid, and caprylic acid, as penetration enhancers for the iontophoretic delivery of drugs.
Thus, there is a continuing need to provide transdermal electrotransport enhancers that provide increased rates of delivery of agents, such as drugs or precursors thereof, in the absence of detrimental effects, such as excessive electric current, to the patient.